PROJECT ABSTRACT Approximately 30.1 million people in the United States suffer from diabetes and our most powerful anti- diabetic medications increase the risk for hypoglycemia. In addition to interfering with the intensity of insulin therapy and glycemic control, severe hypoglycemia causes 4-10% of deaths in patients with type 1 diabetes. One episode of hypoglycemia increases the risk of recurrent hypoglycemia (RH) and can promote hypoglycemia associated autonomic failure (HAAF), which impairs the activation of the sympathetic nervous system and the release of glucose-mobilizing hormones by which the counter-regulatory response (CRR) combats hypoglycemia. The ventromedial hypothalamic nucleus (VMN) represents a crucial mediator of the CRR, but contains many distinctly-acting neural populations. The molecular identity of the CRR-mediating VMN neurons has remained undefined, preventing their study. Recent work in the Myers lab has revealed that the cholecystokinin b receptor (CCKBR)-expressing subpopulation of VMN neurons (VMNCCKBR cells) mediate the CRR: activating these cells increases blood glucose, while silencing them abrogates the CRR. Importantly, we also found that RH impairs the ability of VMNCCKBR neurons to raise blood glucose. The goals of this proposal are to understand the regulation of VMNCCKBR neurons and to test the hypothesis that the lesion in HAAF lies within the VMNCCKBR neural circuitry. We aim to define the afferent and direct mechanisms by which hypoglycemia activates VMNCCKBR neurons and the potential dysregulation of these systems by HAAF. These studies will reveal the neural mechanisms that mediate the CRR and will provide insight into the pathophysiology of HAAF, thus permitting the design of treatments to prevent severe hypoglycemia and permit tight glycemic control. As a physician-scientist, my desire to improve the care of my patients and advance medical science drives my research focus. I aim to become an independent investigator studying the neuronal networks that contribute to the control of blood glucose and which may be pathophysiologically altered in diabetes and related metabolic diseases. The work proposed in this application will allow to me develop the technical skills and conceptual framework to ask important questions about the central control of metabolism, complementing the molecular biology and genetic techniques that I developed during my graduate work. Training in the Myers lab at the University of Michigan provides many opportunities for professional development, including interactions with other leading scientists in the field (via seminars, research presentations and lab meetings) and guided experiences with grant writing, paper writing and reviewing scientific journal articles. I will also receive guidance through the University of Michigan Department of Internal Medicine Physician Scientist Training Program (PSTP), which provides support through regular peer and faculty meetings and is committed to developing young physician scientists into successful faculty members.